P1136: FIRST INTERIM ANALYSIS OF A PHASE 1 STUDY OF ZANUBRUTINIB PLUS LENALIDOMIDE IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA
Authors: Huilai Zhang, Ying Cheng, Hai-Yan Yang, Liling Zhang, Liqun Zou, Ye Guo, Junning Cao, Huiqiang Huang, Zhao Wang, Sha Huang, Zhiyu Liang, Jiaoyan Lyu, Yiqian Fang, Aileen Cohen, Keshu Zhou
Journal: HemaSphere (2023)

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: Effective therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are limited in China, especially for patients who are ineligible for high-dose therapy/stem cell transplantation (HDT/SCT). Preclinical data suggest synergy of lenalidomide with zanubrutinib, a potent and selective Bruton tyrosine kinase inhibitor approved for various B-cell malignancies. Aims: To present interim analysis results of an ongoing phase 1, open-label, dose-escalation/expansion study of zanubrutinib + lenalidomide in R/R DLBCL (NCT04436107). Methods: Patients with R/R DLBCL ineligible for HDT/SCT with ≥1 prior line of adequate systemic therapy were enrolled. Dose escalation (part 1): Lenalidomide 15 mg, 20 mg, or 25 mg orally once daily on days 1-21 of each 28-day cycle. Dose expansion (part 2): Lenalidomide 25 mg. Zanubrutinib 160 mg was given orally twice daily continuously in parts 1 and 2. Primary endpoints were safety and recommended phase 2 dose (RP2D) of lenalidomide (part 1) and overall response rate (ORR) by investigator based on Lugano classification (part 2). Interim analysis was performed when the 19th patient in part 2 completed first tumor assessment. Patients who received lenalidomide 25 mg (RP2D) in parts 1 and 2 were analyzed separately. Results: As of November 8, 2022, 46 patients were treated and included in interim analysis (27 in part 1; 19 in part 2; 30 at RP2D). Median age was 60 years (range, 29-82), 83% had stage III-IV disease, 37% had refractory disease, 70% had non-germinal center B-cell (non-GCB) like disease; median number of prior systemic therapies was 1 (range, 1-5). Median exposure to zanubrutinib and lenalidomide was 3.9 months (range 0.4-24.9), median follow-up was 6.6 months (range 0.5-25.5). ORR was 46% overall (95% CI: 30.9-61.0; complete response [CR]: 24%) and 57% at RP2D (95% CI: 37.4-74.5; CR: 30%). At RP2D, ORR was 61% (95% CI: 38.5-80.3; CR: 35%) for patients with non-GCB disease and 50.0% (95% CI: 11.8-88.2; CR: 17%) for GCB. At RP2D, median duration of response was not reached and 6-months event-free rate was 59% (95% CI: 23.8-82.8). Median progression-free survival was 5.5 months (95% CI: 2.8-not estimable) with a 9-month event-free rate of 37% (95% CI: 17.6-57.4). Overall, 46 (100%) patients experienced ≥1 treatment-emergent adverse event (TEAE). At RP2D, grade ≥3 TEAEs occurred in 60% of patients, most commonly neutrophil count decreased (43%), white blood cell count decreased (23%), and pneumonia (13%). One patient (2%) had febrile neutropenia (grade 3) but recovered within 2 days. TEAEs led to discontinuation of both lenalidomide and zanubrutinib in 2 patients (cardiopulmonary failure unrelated to treatment [part 1, lenalidomide 20 mg], pulmonary embolism [part 1, lenalidomide 25 mg]) and discontinuation of lenalidomide in 2 patients (platelet count decreased [part 1, lenalidomide 20 mg], rash [part 2]). Two TEAEs leading to death were reported, unrelated to treatment. Summary/Conclusion: Zanubrutinib 160 mg plus lenalidomide 25 mg combination showed an acceptable safety profile with promising efficacy. Further evaluation of the combination in a larger sample size is planned in future analysis. Keywords: Diffuse large B cell lymphoma, Non-Hodgkin’s lymphoma, Phase I, B cell